A multi-omics and functional investigation of brains lacking full-length dystrophins

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder characterized by progressive muscle degeneration, severe inflammation, and premature death of young adults. In addition to physical disability, DMD presents largely non-progressive neuropsychiatric abnormalities, impacting patient compliance with treatment and overall quality of life for both patients and their families. The disease arises from mutations in the DMD gene, which encodes structurally and functionally distinct dystrophins. Notably, individuals with DMD lack full-length isoforms present in crucial brain regions, including the hippocampus and cerebral cortex (Dp427c), and cerebellar Purkinje cells (Dp427p). Understanding the consequences of full-length isoform loss is imperative for developing targeted interventions. While previous studies uncovered certain abnormalities, such as altered GABAergic synapses, they do not fully account for all observed symptoms. Here, we employed transcriptomics and proteomics to investigate molecular aberrations resulting from full-length dystrophin loss in the brains of the mdx mouse model of DMD. By analysing brains at 10 days and 10 weeks, we aimed to differentiate between intrinsic developmental changes and those induced by inflammatory mediators crossing the permeable dystrophic blood-brain barrier. Our integrated approach, combining RNA-sequencing with genome-scale metabolic analyses and tandem mass spectrometry, revealed differential expression of genes and proteins, along with enriched pathways in specific dystrophic brain regions. These include mitochondrial, metabolic dysregulation, and RNA splicing alterations. Validation through qPCR, immunodetection, and functional assays further supported these observations. Importantly, our data suggest that some of these alterations may be amenable to therapeutic intervention, offering potential avenues for mitigating brain defects in DMD.